Epidemiology and Burden of Invasive Fungal Infections in the Countries Of

Home , Invasive candidiasis

Journal of Infection and Public Health 13 (2020) 2080–2086

Contents lists available at ScienceDirect

Journal of Infection and Public Health

j ournal homepage: http://www.elsevier.com/locate/jiph

Original Article

Epidemiology and burden of invasive fungal infections in the

countries of the Arab League

a,1 b,1 b,∗

Joumana Kmeid , Jean-Francois Jabbour , Souha S. Kanj

Division of Infectious Diseases, Department of Internal Medicine, Keserwan Medical Center, Ghazir, Lebanon

Division of Infectious Diseases, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon

a r a

t b

i c s t

l e i n f o r a c t

Article history: The burden of invasive fungal infections is alarming worldwide. The aim of this paper is to review the

Received 10 January 2019

published literature and evaluate the knowledge gap pertaining to studies on invasive fungal infections

Received in revised form 8 May 2019

in the countries of the Arab League. Few countries from this region have published reports. The most

Accepted 9 May 2019

commonly studied invasive fungal infections is invasive candidiasis. Candida albicans remains overall

the most common causative pathogen (33.8–60%), however, non-albicans Candida species are increasing.

Keywords:

Antifungal susceptibility testing is non-standardized across the published studies. Data on aspergillo-

Mycoses

sis and other fungal infections is scarce. This sheds light on the need for standardized surveillance in

Invasive fungal infections

Candidiasis the region encompassing more countries of the Arab League to guide diagnostic approach and empiric

Aspergillosis therapy.

for Health Sciences. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction Method

Invasive fungal infections such as invasive candidiasis (IC) and We searched PubMed, ScienceDirect, Ovid and Scopus using the

invasive aspergillosis (IA) constitute a changing and expanding keywords Candida, Aspergillus and fungal infection and each of

public health problem worldwide, including the Arab world [1,2]. the countries from the Arab League (Algeria, Bahrain, Egypt, Iraq,

These infections are considered to be a burden on healthcare due to Jordan, Kuwait, Lebanon, Libya, Morocco, Palestine, Qatar, King-

their association with high morbidity, mortality, and costs of care dom of Saudi Arabia (KSA), Syria, Tunisia, the United Arab Emirates

[3]. (UAE), and Yemen), as well as the MeshTerms “Mycoses” and single

The epidemiology of invasive fungal infections is affected by subheadings of Arab League countries from “Middle East”. Further

many factors including patient-related and environmental consid- information was gathered from abstracts presented at international

erations, both of which differ depending on the geographic region. meetings such as the European Congress of Clinical Microbiology

There is a wealth of information on the epidemiology of invasive and Infectious Disease (ECCMID), ID week, and Interscience Con-

fungal infections from developing countries [4,5] with variability ference on Antimicrobial Agents and Chemotherapy (ICAAC) [7,8].

among continents and countries within the same continent [6]. We excluded most case reports, pure molecular and phylogenetic

Knowledge of the local epidemiology is always desirable to guide analyses, and data from the neonatal population.

diagnosis and prompt therapy. Such data from the Arab world

is scarce. This review aims to summarize the published informa- Results

tion on invasive fungal infections, mostly invasive candidiasis and

invasive aspergillosis, in countries of the Arab League, including Most of the published studies in this region evaluated IC infec-

demographics, species of Candida and Aspergillus infection, sus- tions and more speciﬁcally candidemia. Most of the studies were

ceptibility proﬁles, and patient outcomes. mainly retrospective chart reviews [9–20] while the remainder

were observational epidemiological studies [21–27]. All of the

investigations took place in large tertiary care centers including

multiple intensive care units (ICUs), burn units, and cancer wards

with pediatric, adult, and elderly patients.

∗ KSA hosted more than half of the research projects followed by

Corresponding author.

Qatar [13,21], Lebanon [14], Kuwait [18,23], UAE [15], Bahrain [17],

E-mail address: [email protected] (S.S. Kanj).

Both authors contributed equally. Jordan [25], Algeria [26], Tunisia [19], Iraq [8], and Egypt [27,29].

https://doi.org/10.1016/j.jiph.2019.05.007

CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

J. Kmeid et al. / Journal of Infection and Public Health 13 (2020) 2080–2086 2081

The different study periods ranged from 5 to 10 years extending was found to be resistant to ﬂuconazole in Kuwait [30]. Seventy

from 1991 till 2017 with a variable number of clinical isolates, three percent of the isolates in this study were also resistant to

ranging from 60 to 652. voriconazole, 23% resistant to ampho B and only 1 isolate out the

The burden of serious fungal infections in the Arab world was 56 C. auris isolates was resistant to echinocandins.

estimated to affect 1.41 [26], 1.9 [25], and 2.1% [7] of the pop- The annual rates of IC infection per 1000 discharges per year

ulation each year in Algeria, Jordan, and KSA respectively, with did not follow a similar pattern among the different studies. Some

infections including candidemia, invasive aspergillosis, and other authors reported a signiﬁcant increase over the study years [9],

fungal infections. In one study from Egypt, the rate of invasive whereas others observed that the annual incidence was constant

fungal infection was 8.3% in cancer patients [29]. during the study period [15]. In KSA, the median rate of IC was

as low as 0.45 cases per 1000 hospital discharges per year in one

Candida infection study [11], and it was up to 1.65 cases per 1000 hospital discharges

per year in another [9]. In UAE, however, the median rate was 0.77

Invasive candidiasis, deﬁned mainly as positive blood cases per 1000 hospital discharges per year, and it differed between

[10–13,15,16,22,23] or tissue [9] culture for Candida spp., is 4.51 for cancer patients and 0.33 for those with non-malignant

the most studied fungal infection in the countries of the Arab conditions [15]. Another Saudi study reported that Candida spp.

League. Some studies included peritonitis, intraocular candidiasis constituted 4% of positive blood cultures and was listed as the sixth

[7,21,27], or Candida spp. cultured at any site regardless of the leading cause of hospital-acquired bloodstream infections [16].

clinical picture [14]. Risk factors associated with candidemia were the following:

The most common Candida species isolated was Candida albi- central venous catheter, ICU stay, broad-spectrum antibiotics

cans, ranging from 22.3% to 60% (Table 1). It was observed that [11,15], healthcare-associated infection [11], total parenteral nutri-

the prevalence of non-albicans Candida spp. increased over the tion [11], and age less than 1 year and more than 60 years

study years [9,10,14–16] except for one older study [12], where [13]. Risk factors associated with higher mortality were car-

Al Hedaithy et al. found that the prevalence of non-albicans Can- diopulmonary diseases (20%), malignancies (17%), gastrointestinal

dida spp. decreased from 33.3% during the ﬁrst half of the study diseases including surgery (13%), and renal diseases including kid-

to 16.4% during the second half (1991–2000). The most commonly ney transplant (11%) [13].

recovered species were Candida tropicalis (10.8%–37.7% of all Can- Underlying diseases associated with candidemia were the fol-

dida species), Candida glabrata (4.8%–19.2%), Candida parapsilosis lowing: hematologic malignancy [10–12,15], prematurity [12,15],

(7.9%–36.6%), and Candida krusei (0 [13,15]–7.8%) (Fig. 1). Other surgery [11,12], renal disorders [11,12], respiratory infections [12],

less common isolated species included Candida dubliniensis [13], diabetes [12], hepatic disorders [12], neutropenia [11,15], and

Candida famata, Candida lusitaniae, Candida inconspicua [15], Can- burns [11].

dida guilliermondii, Candida zeylanoides, Candida pseuditropicalis, Malignancy, more speciﬁcally hematological, was signiﬁcantly

and Candida orthopsilosi. Recently published reports also included associated with the development of non-albicans candidemia com-

Candida auris [30,31], an emergent resistant threat that has been pared to C. albicans candidemia in one study [10]. In another study,

detected in a single case from UAE, and in multiple cases from C. albicans and C. glabrata were the most frequent Candida spp.

Kuwait, Oman and KSA [27,32]. associated with malignancy [13]. Non-albicans candidemia was

All studies included in the table (Table 1) are from cases of IC associated with higher numbers of antibiotics use and longer length

except for the study by Araj et al. [14]. The nature of the specimen of hospital stay prior to the development of candidemia [11].

indicated in column 6 was a blood specimen for all studies except Crude mortality rate at 30 days ranged between 40.6% [9] and

for the ﬁrst study by Omrani et al. [9] where it is from “any ster- 43% [11], while crude mortality rate at 90 days was found to be

ile site” and the study by Araj et al. where it is from “any clinical 51.8% in one study [9]. Crude mortality rate at 12 months reached

specimen” [14]. 50% for C. albicans and 57.8% for C. non-albicans in another study

Data concerning in vitro antifungal susceptibility testing were from KSA [10], and up to 81.9% in Qatar [21]. Other authors reported

lacking in many of the available studies. When susceptibility testing an overall crude mortality of up to 56.1% [13].

was conducted, different methods were used, and sometimes they While some studies found that there was no statistically sig-

were changed within the same laboratory over the years. E-test was niﬁcant difference between Candida albicans and non-albicans

the most used method for susceptibility testing [9,10,14,23]. Other candidemia in terms of crude mortality [9,15], other studies from

methods included Candifast [10,22], disk diffusion method [10] KSA reported that the mortality rate for C. albicans was 50% versus

and standard broth microdilution method [13,19]. The antifungals 34.8% for the non-albicans (43% for C. glabrata; 48% for C. tropicalis

tested varied as well, and ﬂuconazole, voriconazole, amphotericin and 25% for C. parapsilosis) [11]. In contrast, C. non-albicans can-

B (ampho B), and caspofungin were the most commonly tested. didemia had a signiﬁcantly higher mortality (68–71.4%) [13] than

Susceptibility of C. albicans to ﬂuconazole ranged between 38.5% C. albicans (45.5%) in Qatar, except for C. parapsilosis (40.6%) [13].

[10] and 96.2% [23]. It was only when tested with Candifast that Only one study from KSA compared mortality in infections

the susceptibilities were lower than 50% [10,22]. Other studies caused by ﬂuconazole-resistant Candida strains to those caused by

observed a susceptibility of around 90%. Susceptibility to flucona- fluconazole-susceptible strains and found no statistically signifi-

zole for the Candida non-albicans was as follows: C. tropicalis 11.1% cant difference [9].

[22]–100%, C. glabrata 50%–94.2%, and C. parapsilosis 66.7%–100%. The median time to death or length of stay ranged between 20

Susceptibility of C. albicans to voriconazole ranged between 94 days [15] and 48.36 days [10].

and 100%, and of the C. non-albicans was as follows: C. tropicalis Risk factors associated with higher mortality were the fol-

83%–100%, C. glabrata 74%–100%, and C. parapsilosis 100%. Overall lowing: cardiopulmonary diseases, malignancies, gastrointestinal

susceptibility of Candida ranged between 81 to 100% to caspofun- diseases [13], age [9], and acute renal failure [11,13].

gin and 90–100% to amphotericin [9,10,13,14,19,22,23]. The wide Studies including Candida infections in other than blood were

range of susceptibilities observed may be due to the heterogene- very few. Studies from Qatar [21], Jordan [25] and Egypt [27], cal-

ity of the methods used and mostly to the low number of isolates culated the burden of Candida infection per 100,000 inhabitants.

tested in some studies. For example, only 38 isolates including the Candida peritonitis had a rate of 8, 5 and 0.74 cases per 100,000

different species of Candida were included in a study conducted by inhabitants respectively in Qatar, Egypt, and Jordan. In one study

Osoba et al. [22]. C. auris, an emergent multidrug resistant threat, from Qatar, it was shown that a higher mortality from peritoneal

2082 J. Kmeid et al. / Journal of Infection and Public Health 13 (2020) 2080–2086

Table 1

The distribution of Candida albicans and non-albicans according to the different studies conducted in some of the countries of the Arab League.

Study Year Country Study period No. of isolates Specimen Distribution of Candida n (%)

C. albicans C. tropicalis C. glabrata C. parapsilosis C. krusei

Omrani et al. (SMJ) [9] 2014 SA Riyadh 2003–2012 (10 y) 652 Any sterile 252 (38.7%) 123 (18.9%) 106 (16.3%) 82 (12.6%) 9 (1.4%)

PSMMC site

Thaqaﬁ et al. (IJID) [10] 2014 SA Jeddah 8 y 252 Blood 86 (34.1%) 39 (15.5%) 23 (9.1%) 30 (11.9%) 10 (4%)

Al Tawﬁq (IJID) [11] 2007 SA Armco 1996–2004 (9 y) 98 Blood 52 (53) (19%) (7%) (16%) (2%)

Al Jasser and Elkhizzi 2004 SA Riyadh 1996–2002 (7 y) 294 Blood 149 (50.7%) 61 (20.7%) 21 (7.1%) 32 (10.9%) 23 (7.8%)

(SMJ) [16] Armed Forces

Al Hedaithy (Mycoses) 2003 SA Riyadh 1991–2000 (10 y) 189 Blood (50.3%) (27%) (7.4%) (7.9%) (3.2%)

[12] KKUH

Osoba et al. (SMJ) [22] 2003 SA Jeddah 1998–2002 (4 y) 83 Blood 38 (46%) 9 (10.8%) 4 (4.8%) 9 (10.8%) 5 (6%)

Taj Aldeen Mycoses 2015 Qatar 2009–2014 (6 y) 288 Blood Species [21] distribution

not speciﬁed

Taj Aldeen et al. 2014 Qatar 2004–2010 (7 y) 187 Blood 68 (33.8%) 36 (17.9%) 38 (18.9%) 34 (26.9%) 0

(Infection) [13]

Araj et al. (JIDC) [14] 2015 Lebanon 9 y 247 Any clinical 61 (24.7%) (34–45%) (25–36%) (9–22%) (5–11%)

specimen

Mokaddas et al. (JMM) 2007 Kuwait 1996–2005 10 y 607 Blood 240 (39.5%) 75 (12.4%) 34 (5.6%) 186 (30.6%) 10 (1.6%)

[23]

Khan and Chugh 2000 Kuwait 1994–1998 141 Blood 48 (34%) 15 (10.6%) 4 (2.8%) 45 (31.9%) 10 (7%)

(IJCDAS) [18]

Ellis et al. (Medical 2003 UAE 1995–2001 (6 y) 60 Blood 27 (45%) 9 (15%) 3 (5%) 3 (5%) 0

Mycology) [15]

Arrache et al. (JMM) 2016 Algeria 2004–2014 (10 y) 65 Blood 20 (31.6%) 15 (23.3%) 0 24 (36.6%) 2 (3.3%)

[20]

Sellami et al. (Mycoses) 2010 Tunisia 2006–2009 (3 y) 130 Blood 29 (22.3%) 49 (37.7%) 25 (19.2%) 16 (12.3%) 4 (3.1%) [19]

The study by Araj et al. included non-invasive isolates.

Fig. 1. The distribution of Candida albicans and non-albicans in candidemia in some countries of the Arab world.

dialysis-related peritonitis was associated with Candida infection In contrary to the United States of America (USA) and Latin

and pseudomonal infection in comparison to other bacterial infec- American countries, where Candida non-albicans constitutes above

tions [33]. Intraocular candidiasis had a rate of 2.05 cases per 50% of candidemia cases [37], C. albicans remains the most com-

100,000 inhabitants in Qatar [21] compared to 14 cases per 100,000 monly isolated species in blood in the Arab League countries. This

inhabitants in Egypt [27]. Individuals at risk were patients with data is similar to the ones from European and Asia-paciﬁc stud-

ICU stay, a history of malignancy, prior surgery, a history of renal ies [38,39]. This difference could be due to the different studied

transplant and immunosuppression. patient populations, such as cancer patients on prophylaxis versus

In concordance with the data from the western countries, can- ICU patients, or to the different practices of antifungal use in the

didemia is the most investigated fungal infection in the Arab League regions. As in the rest of the world, a trend towards an increasing

countries. Moreover, as in studies from United States (US) hospitals proportion of Candida non-albicans is being observed in the region.

[34] and multinational studies [35–37], Candida species are among The risk factors for candidemia in the region were similar to

the leading pathogens of healthcare-associated bloodstream infec- those found in western studies. Attributable mortality of can-

tions [16]. didemia, calculated as 47% [37] in western countries, is generally

J. Kmeid et al. / Journal of Infection and Public Health 13 (2020) 2080–2086 2083

similar to the crude mortality at 30 days in the Arab League coun- revealed a signiﬁcant inverse correlation with ampho B (p < 0.001)

tries. and voriconazole (p < 0.003) [48].

Another study from KSA [7] evaluated the in vitro suscepti-

Aspergillus infection bility to ampho B, itraconazole, voriconazole, posaconazole, and

caspofungin of 250 clinical isolates of Aspergillus spp. Antifungal

Published regional studies on IA are very limited compared to susceptibility testing was performed by the Clinical and Laboratory

IC. Hence, regional clinical practice guidelines for the treatment Standards Institute (CLSI) M38-A broth dilution method. From the

and diagnosis of aspergillosis are mostly based on international 250 isolates, 114 were Aspergillus niger, 98 were A. ﬂavus, 23 were A.

studies [21,40]. In a review on IA in developing countries, includ- fumigatus, and 15 were A. terreus. A. ﬂavus was mainly isolated from

ing the Middle East, sino-orbital or cerebral aspergillosis and cases of fungal rhinosinusitis. About 70% of A. niger was cultured

Aspergillus endophthalmitis were reported to be emerging dis- from ear swabs and from nails. A. fumigatus was cultured more from

eases with Aspergillus ﬂavus being the predominant species. This respiratory specimens. All isolates were susceptible to itraconazole,

is thought to be due to a higher prevalence of the fungus in the voriconazole, posaconazole, and caspofungin. However, decreased

environment [41]. susceptibility to ampho B was noticed with A. ﬂavus and A. terreus.

Whereas fungal asthma was reported at a rate of 60.2 cases per For ampho B, about 40% of A. ﬂavus had an MIC of >2.0 mg/l and

100,000 inhabitants in one study from Qatar, IA was found to have about 70% of A. terreus have an MIC of 4.0 mg/l. Voriconazole and

a rate of only 0.6 cases per 100,000 inhabitants [21]. Another study posaconazole were the most effective agents [7].

from KSA reported a rate of 7.6 per 100,000 inhabitants [7]. A study from Tunisia [49] tested ampho B, itraconazole,

In KSA, invasive aspergillus paranasal infection was found in one voriconazole, posaconazole and caspofungin against 48 Aspergillus

study to be mostly associated with A. ﬂavus in immunocompetent isolates (17 A. niger, 18 A. ﬂavus, 9 Aspergillus tubingensis, 1

patients and complete surgical evacuation followed by antifun- Aspergillus westerdijkiae, and 1 Aspergillus ochraceus) with the E-

gal therapy was associated with relapse-free disease [42]. Another test. MICs were above the epidemiological cut-off values for ampho

study from Bahrain found that IA was diagnosed in 16 out of 60 B in 67% of A. ﬂavus strains, for caspofungin in 22% of A. ﬂavus strains,

patients with positive Aspergillus cultures [17], where the pre- and for itraconazole in 22% of A. tubingensis strains. Voriconazole

dominant species was Aspergillus fumigatus (53%) and the lungs and posaconazole MICs were below the epidemiological cut-off

were the most common site of infection. Mortality was as high as values for all strains.

40%, however, adequate antifungal therapy with voriconazole was When exposed to caspofungin, 42% of the strains exhibited trail-

not initiated in all the cases. A retrospective study from Kuwait ing effect and 38% paradoxical growth. Trailing effect occurred in

identiﬁed 11 cases of IA from 1994 to 1998, including 5 cases of 61% of A. ﬂavus strains and paradoxical growth in 62% of Aspergillus

A. fumigatus, 3 cases of A. ﬂavus and 3 cases of Aspergillus terreus, section Nigri strains.

mostly in renal transplant recipient patients [18]. Albeit there are no published data from the region on the

A recent descriptive study from 5 hospitals in KSA and Lebanon treatment of IA, a recent international study, including a center

reported 102 cases of invasive fungal infection due to Candida and from Lebanon where 20 patients were recruited from each cen-

Aspergillus species from 2011 to 2012 [1]. Among the 102 cases, ter, concluded that patients with IA who received primary therapy

only 80 cases were evidenced by culture and only 10 of which with voriconazole-containing regimen had an improved response

yielded Aspergillus spp. The overall mortality rate was found to be and survival compared with non-voriconazole containing regimens

42%. Mortality due to Aspergillus invasive infection alone was not [50].

calculated. In a prospective study from Egypt, in 960 patients with In comparison with global data, it seems that countries of

hematologic malignancies, invasive fungal infection was diagnosed the Arab League are not yet encountering the same increasing

in 8.3% of the patients, 19 (2%) of them had IA [29]. voriconazole resistance in A. fumigatus and other Aspergillus spp.

A three-year prospective study carried out in Tunisia in patients The predominance of A. ﬂavus, similar to other surrounding coun-

with hematologic malignancies found that among 105 neutropenic tries [51] and other studies from developing countries [41] and the

patients, 16 were diagnosed with probable and 13 with possible relatively high frequency of ampho B resistant strains in A. ﬂavus,

IA [43]. A. ﬂavus was the most frequently isolated (79.2%). Envi- makes voriconazole best adapted as a ﬁrst-line treatment for inva-

ronmental screening for fungal pathogens (690 samples) found sive aspergillosis in countries of the Arab League.

that Aspergillus spp. was the third most frequently isolated fungal

pathogen (18%). PCR sequencing of 30 A. ﬂavus isolates detected Mucormycosis

from clinical and environmental samples conﬁrmed the mycologi-

cal similarity [43]. Another study from northern Algeria describes Data on mucormycosis in countries of the Arab league is very

a rate of 7.7% of IA in neutropenic patients [26]. scarce and mostly consists of individual case reports [52,53]. In one

The rate of recovery of antifungal-resistant Aspergillus spp. is study from Qatar, mucormycosis was found to have a rate of 1.23

increasing in many countries, mostly in Europe [44–47]. Data on cases per 100,000 inhabitants [21]. In Iraq, Jordan, and Algeria, the

antifungal susceptibility of Aspergillus spp. from the Arab League annual rates of mucormycosis were estimated at about 0.2 cases per

countries is scarce. One study from Kuwait [30,48] analyzed 99 100,000 [25]. KSA had an even lower rate of 0.034 cases per 100,000

A. ﬂavus isolates, including clinical specimens, for susceptibility [25]. A recent retrospective chart review at a tertiary care center in

testing to 6 antifungal agents by E-test and for molecular iden- Lebanon identiﬁed 20 cases of mucormycosis between 2008 and

tiﬁcation. The identity of all clinical and environmental isolates 2018 [54]. In this study and an older one from Lebanon in 2006

was conﬁrmed as A. ﬂavus species by combined analysis of ␤- [24], patients with mostly rhino-orbital or pulmonary involvement

tubulin and calmodulin genes. The mean MIC90 (␮g/ml) values on were found to have an underlying hematologic malignancy and/or

RPMI medium for ampho B, voriconazole, posaconazole, anidu- diabetes mellitus as risk factors. Both studies observed that the

lafungin, micafungin, and caspofungin were 3, 0.25, 0.25, 0.002, number of mucormycosis cases per 10,000 hospital admissions

0.002 and 0.032, respectively. No environmental isolate exhibited increased signiﬁcantly over the study years. All-cause mortality

an MIC value of >2 ␮g/ml for ampho B. For clinical isolates, the was found to be 60% [54]. Cause of death, however, was directly

zone of inhibition diameters for ampho B and voriconazole ranged attributed to mucormycosis in only 20% of cases, despite aggres-

from 7 to 16 mm and 24 to 34 mm, respectively. Linear regression sive treatment with liposomal amphotericin B, posaconazole and

analysis between E-test MIC values and disk diffusion diameters surgical interventions [54].

2084 J. Kmeid et al. / Journal of Infection and Public Health 13 (2020) 2080–2086

Table 2

Another case series from Tunisia reported 5 cases mostly in dia-

Availability of data on serious fungal infections in countries of the Arab League.

betic patients. Rhizopus arrhizus was the most commonly isolated

species followed by Lichteimia corymbifera [55]. All patients were Estimated burden

of serious fungal

treated with ampho B deoxycholate as liposomal products were not

infections

available in the country. Two of the patients died.

The scarcity of the data makes it difﬁcult to compare the epi- √√IC IA MM

Algeria ×

demiology of mucormycosis in our region to international studies. √

Bahrain × ×

√ √ √

However, some of the countries of the Arab world, including

Egypt √

Lebanon are currently participating in international registries on × ×

Iraq √√√

mucormycosis overseen by the European Confederation of Medi- Jordan √ √

Kuwait ×

cal Mycology ECMM [56]. This registry would be of great value in √

√ √

Lebanon

comparing and contrasting epidemiological and clinical variations

Libya × × ×

among regions and countries.

Morocco × × ×

Palestine × × ×

√ √ √

Other fungal infections Qatar √

√ √

KSA

Syria × × ×

√ √ √

The annual rates of cryptococcal meningitis and pneumocys-

Tunisia √√

tis pneumonia in Qatar was found to be respectively 0.43 and 0.8 UAE ×

cases per 100,000 inhabitants [21], with 125 cases of pneumocystis Yemen × × ×

pneumonia detected each year [27]. There are no published reports

IC: Invasive Candidiasis; IA: Invasive Aspergillosis; MM: Mucormycosis; KSA: King-

on these infections from other countries of the Arab League. It is

dom√ of Saudi Arabia; UAE: United Arab Emirates.

estimated that the annual incidence of cryptococcal meningitis is : Availability of local epidemiological studies that estimate the burden of the dis-

ease.

less than 500 cases annually. This is lower than the annual inci-

×: Lack of studies that estimate the burden of the disease. Minor case reports that

dence in the United States, which ranges between 2501 and 5000

do not provide an epidemiological analysis are excluded.

cases, and much lower than the highest incidence that is found

in Sub-Saharan Africa with more than 25,000 cases annually [57].

lack of routine susceptibility testing and unavailability of therapeu-

Fungal infections due to other organisms such as Fusarium spp.

tic drug level monitoring for azoles in many countries in the region

were found to have a low rate of 1.68 cases per 100,000 inhabi-

make the management of invasive fungal infection very difﬁcult

tants in Qatar, including few cases of Fusarium cornea infections

especially in immunocompromised patients with many comorbidi-

[21]. Uncommon serious bloodstream fungal pathogens reported

ties.

in one Qatari study were: Kluyveromyces marxianus, Lodderomyces

elongisporus, Lindnera fabianii, Meyerozyma guilliermondii, Pichia

Conclusion

kudriavzevii, Yarrowia lipolytica, Clavispora lusitaniae, and Wicker-

hamomyces anomalus [58]. Gastrointestinal basidiobolomycosis is

Invasive fungal infections remain a major cause of morbid-

another rare serious fungal infection with only 89 cases published

ity and mortality worldwide. In light of the limited available

worldwide since 1964 including 39 cases from countries of Arab

data from the countries of the Arab League, there is a tremen-

League (KSA, Kuwait, Oman, and Qatar) [59].

dous need to conduct systemic standardized surveillance in

Another rare fungal organism that has been described in the

order to help establish regional guidelines for the diagnosis and

region to cause invasive infection is Rhinocladiella mackenziei (for-

management.

merly Ramichloridium mackenziei) [60,61]. Cases of brain abscesses

Studies on antifungal susceptibility are scarce, and the variety

have been described mostly from KSA, but also from Kuwait, Qatar,

of methods used reﬂects the limited diagnostic resources in our

and Oman among the countries of Arab League [60–62]. This is

region. Future studies should aim at standardizing the identiﬁca-

a devastating infection affecting immunocompetent patients with

tion and susceptibility testing. In addition, antifungal stewardship

poor prognosis and a mortality rate of more than 80% [62].

should be practiced to curtail the potential emergence of resistance

Challenges in this region.

Funding

Many challenges remain concerning invasive fungal infections

in the region. There is a vast discrepancy on the availability of the

No funding sources.

resources in the various countries. Rich countries in the region, for

example, have state of the art laboratory facilities [21,23,30] and

Competing interests

many available therapeutic options [47], whereas others lack basic

laboratory tests and have only old antifungal agents (ampho B and

None declared.

ﬂuconazole) available for use [47].

There is an evident lack of standardized epidemiological studies

Ethical approval

in some of the Arab countries (Table 2). Countries such as Egypt,

Jordan, Lebanon, Qatar, KSA, and Tunisia generally have published

Not required.

data that estimates the burden of invasive fungal infections. Other

countries, however, such as Libya, Morocco, Palestine, and Yemen

are almost completely devoid of such studies. The emergence of References

new/rare Candida spp. in the region, the problems with proper

[1] Alothman AF, Althaqaﬁ AO, Matar MJ, Moghnieh R, Alenazi TH, Farahat FM, et al.

identiﬁcation methods, and the discrepancy at times between phe-

Burden and treatment patterns of invasive fungal infections in hospitalized

notypic and molecular identiﬁcation remain a signiﬁcant challenge. patients in the Middle East: real-world data from Saudi Arabia and Lebanon.

In addition, the reduced antifungal susceptibility to ampho B, the Infect Drug Resist 2017;10:35–41.

J. Kmeid et al. / Journal of Infection and Public Health 13 (2020) 2080–2086 2085

[2] Alothman AF, Al-Musawi T, Al-Abdely HM, Salman JA, Almaslamani M, Yared [33] Shigidi MM, Fituri OM, Chandy SK, Asim M, Al Malki HA, Rashed AH. Microbial

N, et al. Clinical practice guidelines for the management of invasive Candida spectrum and outcome of peritoneal dialysis related peritonitis in Qatar. Saudi

infections in adults in the Middle East region: expert panel recommendations. J Kidney Dis Transpl 2010;21(1):168–73.

J Infect Public Health 2014;7(1):6–19. [34] Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Noso-

[3] Kim A, Nicolau DP, Kuti JL. Hospital costs and outcomes among intravenous comial bloodstream infections in US hospitals: analysis of 24,179 cases from a

antifungal therapies for patients with invasive aspergillosis in the United States. prospective nationwide surveillance study. Clin Infect Dis 2004;39(3):309–17

Mycoses 2011;54(5):e301–12. (1537–6591 (Electronic)).

[4] Webb BJ, Ferraro JP, Rea S, Kaufusi S, Goodman BE, Spalding J, et al. Epidemiol- [35] Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L.

ogy and clinical features of invasive fungal infection in a US health care network. Clinical practice guideline for the management of candidiasis: 2016 update by

Open Forum Infect Dis 2018;5(8), ofy187-ofy187. the infectious diseases society of america. Clin Infect Dis 2016;62(4):e1–50.

[5] Enoch D, Ludlam H, Brown N. Invasive fungal infections: a review of epidemi- [36] Kett DH, Azoulay E, Echeverria PM, Vincent JL. Candida bloodstream infec-

ology and management options. J Med Microbiol 2006;55(7):809–18. tions in intensive care units: analysis of the extended prevalence of infection

[6] Horn DL, Neofytos D, Anaissie EJ, Fishman JA, Steinbach WJ, Olyaei AJ, in intensive care unit study. Crit Care Med 2011;39(4):665–70 (1530-0293

et al. Epidemiology and outcomes of Candidemia in 2019 patients: data (Electronic)).

from the prospective antifungal therapy alliance registry. Clin Infect Dis [37] Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis: a persistent pub-

2009;48(12):1695–703. lic health problem. Clin Microbiol Rev 2007;20(1):133–63.

[7] Albarrag AM, Al-Abdely HM, Abu Khalid NF, Denning DW.Poster at the 54 [38] Pfaller MA, Moet GJ, Messer SA, Jones RN, Castanheira M. Geographic varia-

Interscience Conference of Antimicrobial Agents and Chemotherapy. 2014. tions in species distribution and echinocandin and azole antifungal resistance

[8] Mohammad K, Ismael H, Shekhany K, Al-Attraqhchi A, Abdullah S, Ali B, et al. rates among Candida bloodstream infection isolates: report from the SEN-

Burden of serious fungal infection in Iraq Barcelona, Spain, 10–13 May. Pro- TRY Antimicrobial Surveillance Program (2008 to 2009). J Clin Microbiol

ceedings of the 24 European Congress of Clinical Microbiology and Infectious 2011;49(1):396–9.

Diseases (ECCMID) 2014. Volume: ECCMI-2416. [39] Bassetti M, Merelli M, Ansaldi F, de Florentiis D, Sartor A, Scarparo C. Clinical

[9] Omrani AS, Makkawy EA, Baig K, Baredhwan AA, Almuthree SA, Elkhizzi NA, and therapeutic aspects of candidemia: a ﬁve year single centre study. PLoS

et al. Ten-year review of invasive Candida infections in a tertiary care center in One 2015;10(5):e0127534.

Saudi Arabia. Saudi Med J 2014;35(8):821–6. [40] Al-Abdely HM, Alothman AF, Salman JA, Al-Musawi T, Almaslamani M, Butt AA.

[10] Al Thaqaﬁ AH, Farahat FM, Al Harbi MI, Al Amri AF, Perfect JR. Predictors and Clinical practice guidelines for the treatment of invasive Aspergillus infections

outcomes of Candida bloodstream infection: eight-year surveillance, western in adults in the Middle East region: expert panel recommendations. J Infect

Saudi Arabia. Int J Infect Dis 2014;21:5–9. Public Health 2014;7(1):20–31.

[11] Al-Tawﬁq JA. Distribution and epidemiology of Candida species caus- [41] Chakrabarti A, Chatterjee SS, Das A, Shivaprakash MR. Invasive aspergillosis in

ing fungemia at a Saudi Arabian hospital, 1996-2004. Int J Infect Dis developing countries. Med Mycol 2011;49 Suppl 1:S35–47 (1460-2709 (Elec-

2007;11(3):239–44. tronic)).

[12] Al-Hedaithy SS. The yeast species causing fungemia at a university hospital in [42] Alrajhi AA, Enani M, Mahasin Z, Al-Omran K. Chronic invasive aspergillosis of

Riyadh, Saudi Arabia, during a 10-year period. Mycoses 2003;46(8):293–8. the paranasal sinuses in immunocompetent hosts from Saudi Arabia. Am J Trop

[13] Taj-Aldeen SJ, Kolecka A, Boesten R, Alolaqi A, Almaslamani M, Chandra P, et al. Med Hyg 2001;65(1):83–6.

Epidemiology of candidemia in Qatar, the Middle East: performance of MALDI- [43] Hadrich, Makni F, Sellami H, Cheikhrouhou F, Sellami A, Bouaziz H. Invasive

TOF MS for the identiﬁcation of Candida species, species distribution, outcome, aspergillosis: epidemiology and environmental study in haematology patients

and susceptibility pattern. Infection 2014;42(2):393–404. (Sfax, Tunisia). Mycoses 2010;53(5):443–7, 1439-0507 (Electronic)).

[14] Araj GF, Asmar RG, Avedissian AZ. Candida proﬁles and antifungal resistance [44] Meis JF, Chowdhary A, Rhodes JL, Fisher MC, Verweij PE. Clinical implications

evolution over a decade in Lebanon. J Infect Dev Ctries 2015;9(9):997–1003. of globally emerging azole resistance in Aspergillus fumigatus. Philos Trans R

[15] Ellis M, Hedstrom U, Jumaa P, Bener A. Epidemiology, presentation, manage- Soc Lond B Biol Sci 2016;371(1709), http://dx.doi.org/10.1098/rstb.2015.0460,

ment and outcome of candidemia in a tertiary care teaching hospital in the pii: 20150460 (1471-2970 (Electronic)).

United Arab Emirates, 1995-2001. Med Mycol 2003;41(6):521–8. [45] Verweij PE, Snelders E, Kema GH, Mellado E, Melchers WJ, et al. Azole resistance

[16] Al-Jasser AM, Elkhizzi NA. Distribution of Candida species among bloodstream in Aspergillus fumigatus: a side-effect of environmental fungicide use? Lancet

isolates. Saudi Med J 2004;25(5):566–9. Infect Dis 2009;9(12):789–95.

[17] Alsalman J, Zaid T, Makhlooq M, Madan M, Mohamed Z, Alarayedh A, et al. A [46] Lass-Florl C, Lass-Flörl C, Griff K, Mayr A, Petzer A, Gastl G, Bonatti H, et al. Epi-

retrospective study of the epidemiology and clinical manifestation of invasive demiology and outcome of infections due to Aspergillus terreus: 10-year single

aspergillosis in a major tertiary care hospital in Bahrain. J Infect Public Health centre experience. Br J Haematol 2005;131(2):201–7 (0007-1048 (Print)).

2017;10(1):49–58. [47] Kneale M, Bartholomew JS, Davies E, Denning DW. Global access to antifungal

[18] Khan ZU, Chugh TD. Invasive fungal infections in Kuwait: a retrospective study. therapy and its variable cost. J Antimicrob Chemother 2016;71(12):3599–606.

Indian J Chest Dis Allied Sci 2000;42(4):279–87. [48] Al-Wathiqi F, Ahmad S, Khan Z. Molecular identiﬁcation and antifungal suscep-

[19] Sellami A, Sellami H, Neji S, Makni F, Abbes S, Cheikhrouhou F, et al. Anti- tibility proﬁle of Aspergillus ﬂavus isolates recovered from clinical specimens

fungal susceptibility of bloodstream Candida isolates in Sfax hospital: Tunisia. in Kuwait. BMC Infect Dis 2013;13(1):126.

Mycopathologia 2011;171(6):417–22. [49] Gheith S, Saghrouni F, Bannour W, Ben Youssef Y, Khelif A, Normand AC. In vitro

[20] Arrache D, Madani KH, Achir I, Younsi N, Zebdi A, Bouahri L, et al. Fongémies susceptibility to amphotericin B, itraconazole, voriconazole, posaconazole and

diagnostiquées au laboratoire de parasitologiemycologie du CHU Mustapha caspofungin of Aspergillus spp. isolated from patients with haematological

d’Alger, Algérie. J Mycol Med 2016;2016:237–8. malignancies in Tunisia. SpringerPlus 2014;3:19.

[21] Taj-Aldeen SJ, Chandra P, Denning DW. Burden of fungal infections in Qatar. [50] Hachem R, Batista MV, Kanj SS, El Zein S, Haddad S, Jiang Y, et al. International

Mycoses 2015;58(Suppl. 5):51–7. multicenter experience in the treatment of invasive aspergillosis in immuno-

[22] Osoba AO, Al-Mowallad AW, McAlear AD, Hussein BA. Candidemia and compromised cancer patients. Mediterr J Hematol Infect Dis 2018 [in press].

the susceptibility pattern of Candida isolates in blood. Saudi Med J [51] Hedayati MT, Tavakoli M, Mosazadeh M, Yazdani Charati J, Seyedmousavi SM,

2003;24(10):1060–3. Denning DW. Invasive aspergillosis in Iran: a systematic review and meta-

[23] Mokaddas EM, Al-Sweih NA, Khan ZU. Species distribution and antifungal sus- analysis. The 8th Advances Against Aspergillus, Lisbon Conference Center 2018.

ceptibility of Candida bloodstream isolates in Kuwait: a 10-year study. J Med [52] El Deeb Y, Al Soub H, Almaslamani M, Al Khuwaiter J, Taj-Aldeen SJ. Post-

Microbiol 2007;56(Pt 2):255–9. traumatic cutaneous mucormycosis in an immunocompetent patient. Ann

[24] Al-Ajam MR, Bizri AR, Mokhbat J, Weedon J, Lutwick L. Mucormyco- Saudi Med 2005;25(4):343–5 (0256-4947 (Print)).

sis in the Eastern Mediterranean: a seasonal disease. Epidemiol Infect [53] Venkatesh D, Dandagi S, Chandrappa PR, Hema KN. Mucormycosis in immuno-

2006;134(2):341–6. competent patient resulting in extensive maxillary sequestration. J Oral

[25] Wadi J, Denning DW. Burden of serious fungal infections in Jordan. J Fungi Maxillofac Pathol 2018;22(4):112–6 (0973-029X (Print)).

2018;4(1). [54] El Zein S, El-Cheikh J, El Zakhem A, Ibrahim D, Bazarbachi A, Kanj SS. Mucormy-

[26] Chekiri-Talbi M, Denning DW. Burden of fungal infections in Algeria. Eur J Clin cosis in hospitalized patients at a tertiary care center in Lebanon: a case series.

Microbiol Infect Dis 2017;36(6):999–1004. Infection 2018;46(6):811–21 (1439-0973 (Electronic)).

[27] Zaki SM, Denning DW. Serious fungal infections in Egypt. Eur J Clin Microbiol [55] Bellazreg F, Hattab Z, Meksi S, Mansouri S, Hachﬁ W, Kaabia N. Outcome of

Infect Dis 2017;36(6):971–4. mucormycosis after treatment: report of ﬁve cases. New Microbes New Infect

[29] El-Masry H, Badrawy H, Sayed D, Khalaf MR, El-Mahallawy H. Prevalence and 2014;6:49–52.

description of invasive fungal infection in adults with hematological neo- [56] Skiada A, Lanternier F, Groll AH, Pagano L, Zimmerli S, Herbrecht R. Diagnosis

plasms. SECI Oncol 2014;2(4):48–54. and treatment of mucormycosis in patients with hematological malignancies:

[30] Khan Z, Ahmad S, Al-Sweih N, Joseph L, Alfouzan W, Asadzadeh M. guidelines from the 3rd European Conference on Infections in Leukemia (ECIL

Increasing prevalence, molecular characterization and antifungal drug sus- 3). Haematologica 2013;98(4):492–504.

ceptibility of serial Candida auris isolates in Kuwait. PLoS One 2018;13(4): [57] Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM, et al.

e0195743. Global burden of disease of HIV-associated cryptococcal meningitis: an updated

[31] Emara M, Ahmad S, Khan Z, Joseph L, Al-Obaid I, Purohit P. Candida auris can- analysis. Lancet Infect Dis 2017;17(8):873–81.

didemia in Kuwait, 2014. Emerging Infect Dis 2015;21(6):1091–2. [58] Taj-Aldeen SJ, AbdulWahab A, Kolecka A, Deshmukh A, Meis JF, Boekhout T.

[32] Centers for Disease Control and Prevention, 2019. Available from: https:// Uncommon opportunistic yeast bloodstream infections from Qatar. Med Mycol http://www.cdc.gov/fungal/candida-auris/tracking-c-auris.html-world. 2014;52(5):552–6.

2086 J. Kmeid et al. / Journal of Infection and Public Health 13 (2020) 2080–2086

[59] Pezzani MD, Di Cristo V, Parravicini C, Sonzogni A, Tonello C, Franzetti M, et al. [61] Kanj SS, Amr SS, Roberts GD. Ramichloridium mackenziei brain abscess: report

Gastrointestinal basidiobolomycosis: an emerging mycosis difﬁcult to diagnose of two cases and review of the literature. Med Mycol 2001;39(1):97–102.

but curable. Case report and review of the literature. Travel Med Infect Dis 2019. [62] Yusupov N, Merve A, Warrell CE, Johnson E, Curtis C, Samandouras G. Multiple

[60] Al-Tawﬁq JA, Boukhamseen A. Cerebral phaeohyphomycosis due to Rhin- brain abscesses caused by Rhinocladiella mackenziei in an immunocompe-

ocladiella mackenziei (formerly Ramichloridium mackenziei): case presenta- tent patient: a case report and literature review. Acta Neurochir (Wien)

tion and literature review. J Infect Public Health 2011;4(2):96–102. 2017;159(9):1757–63.